Structure-guided drug screening for mgmt inhibitors in glioblastoma resistance

Glioblastoma is the most aggressive primary malignant tumor of the central nervous system in adults. Treatment consists of surgical resection, followed by radiotherapy and chemotherapy with alkylating agents. Temozolomide (TMZ) is an alkylating agent that acts on the methylation of O6-Guanines, activating the mismatch repair mechanisms and triggering cell apoptosis. The MGMT gene produces an enzyme that corrects the damage to DNA caused by TMZ, leading to treatment resistance. Objective: This study aims to identify and characterize novel compounds with selective inhibitory potential against MGMT using in silico computational methodologies, including screening natural Brazilian compounds from the Nubbe platform. The three-dimensional structure of MGMT was obtained from the RCSB Protein Data Bank and further refined for apo and holo-models of zinc ion using Modeller. The pKa of titratable residues were estimated with H++ and molecular dynamics simulations of 500 ns were performed with GROMACS for both apo and holo-models. Subsequently, molecular docking will be carried out to search for molecules with the potential to interact with active site binding regions, followed by analysis of selected compounds' physicochemical and pharmacological properties. This comprehensive approach aims to identify promising MGMT inhibitors from natural sources that could potentially enhance the therapeutic efficacy of TMZ in glioblastoma patients, offering new avenues for overcoming treatment resistance.